E3

Question 1

Name conventional synthetic DMARDs

- what are they also known as

Answer 1

classical (csDMARD) 
Sulphazalazine
Methotrexate 	
Leflunomide
hydroxylchloroquine

Question 2

Describe Sulphasalazine

• what is it also used to treat
• name the alternative route
• describe mode of action

Answer 2

Combined anti-bacteria & anti-inflammatory
Also used to treat UC
- sulphapyridine: absorbed, metabolised then excreted

Both breakdown products may contribute, as well as intact molecule,
Inhibits B cell activity: reduces IgG and RF production
Inhibition of NFκB translocation to nucleus?
- NF-kB key pathway for transcription of proinflam mediators
- Inhibition of cytokine, chemokine and adhesion molecule synthesis
- Osteoclast formation
(effects on gut bacteria flora on inflammatory cell functions and on immunological process)

Question 3

Describe adverse effects of Sulphasalazine
- what should be regularly tested

pharmacological undesired effects

Answer 3

Skin reactions - rashes
gastro-intestinal intolerance
Hematological effects - especially in patients with RA
- leucopenia
- neutropenia
- Thrombocytopenia
- (if occurs should be discontinued immediately)
Blood counts should be undertaken during first 3 months

Not a very potent or selective drug (affinity moderate- need to use lots of drug),
Therefore the potential for off-target effects high - leads to adverse effects,
However - it works, is cheap and side-effects manageable,
Safe to use in pregnancy (low dose) and can be continued preoperatively
Short half life & minimal immunosuppressive effects

Question 4

Describe Methotrexate

• what does it inhibit
• what does it release
  3. first line treatment for what disease

Answer 4

Defined Mechanisms of Action (differ between high and low doses)
Inhibits dihydrofolate reductase
- Therefore inhibits purine/pyrimidine synthesis, DNA synthesis and cell proliferation, including T-cell and B-cell populations, osteoclasts and fibroblasts
- (cell cycle rest at S1 – doesnt play major role in low doses)
Stimulates the release of adenosine (low dose therapy)
- Adenosine has potent anti-inflammatory effects through A2a and A3 receptors
- purenergic receptors overexpressed in RA - adenosine signalling can downregulate production TNFa production and NF-KB signalling + downreg of activation/ proliferation of T lymphocytes
- Dampening of immune response

3. RA - - Often used in combination with other agents such as sulphasalazine and steroids
   
   • Highly effective in a significant proportion of patients

Question 5

Name adverse effects of Methotrexate

Answer 5

Adverse effects are predictable from inhibition of cell proliferation

• e.g. Bone marrow depression and blood dyscrasias
• Side effects of low dose rarely life threatening - high dose can be
• haematological abnormalities, GI problems, elevation of liver problems, CNS problems e.g. Headaches
• Cant be used during pregnancy

Question 6

What are biologics
what do they target
- what must be checked

Answer 6

(bDMARD)

• Immunomodulatory: target cytokines and immune cells
• Ab designed to target inflammatory mediators
• Before treatment Blood cell count & liver function must be checked

Question 7

Name some targets if bDMARDS

Answer 7

IL6, IL-23, IL-17, IL-1, TGF-B, Th1, B cells, TNFa
- TNFα (produced by T, Bc, synovial macrophages, impt. mediator of joint inflammation,
overexpression can induce cartilage degradation & bone erosion + spontaneous inflammation in rodent models)
IL-1β: recruits & activate other immune cells + initiates/ perpetuates production of degradative enzymes: MMP and PG
- Interleukin 6 (IL-6),
- Interleukin 17 (IL-17)?
(Directly inhibit Tc or Bc function to modify disease progression)

Question 8

Name the two forms of TNFa

Answer 8

Different forms by diff molecular weights

1. Membrane-bound TNFa (26kDa) –> - converted to soluble form by TACE (TNF converting enzyme)
2. Soluble TNFa (17kDa)

Question 9

Name Transcription Products of TNFa Signalling: Pro-inflammatory

Answer 9

(autocrine loop)

• TNFa
• Il-1B
• Upregulation of adhesion molecules (ICAM-1, VCAM-1)
• Cytokines that further enhance the immune response
• Activators of inflammatory pathways (arachidonic acid metabolites, superoxides and NO)

Question 10

What type of Ab is Infliximab

Describe mechanism of Action

Answer 10

Chimeric Ab (25% mouse: 75% human) 
Binds and neutralizes both soluble and membrane bound TNFa - inhibits further activity
Prevents TNF binding to receptor (TNF2) prevents downstream effects e.g. Initiating transcription of NF-KB signalling